Shi Mengling, Wang Cong, Chen Zhen, Zhou Yidan, Yue Liang, Liu Yu, Guo Tiannan, Shang Jun, Xu Haotian, Zhang Yu, Luo Mengcheng, Lei Caoqi
State Key Laboratory of Virology and Biosafety, College of Life Sciences, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, China.
Department of Epidemiology and Biostatistics, School of Public Health, Wuhan University, Wuhan University, Wuhan, China.
Nat Commun. 2025 May 1;16(1):4084. doi: 10.1038/s41467-025-59421-x.
VISA/MAVS is crucial in antiviral innate immunity. Upon RNA virus infection, VISA recruits TBK1 via TRAFs to mitochondria, inducing IRF3 phosphorylation and type I interferons. However, TBK1 recruitment mechanisms via individual TRAFs are unclear. Here, we reveal that PWWP domain-containing 3A (PWWP3A) serves as a negative regulator of RNA virus-triggered signaling. During viral infection, PWWP3A translocates from nucleus to the mitochondria, competing with TRAF6 for binding to VISA, thereby impeding the recruitment of TBK1 and inhibiting IRF3 activation. However, the extent of PWWP3A-mediated inhibition is regulated by the E3 ligase PJA2, which induces PWWP3A degradation post-infection, highlighting the intricate regulatory network in antiviral immunity. Consistently, PWWP3A deficiency enhances antiviral responses, and Pwwp3a mice exhibit elevated levels of type I interferons and displayed greater resistance following RNA virus infection. Together, our findings unveil the inhibitory role of PWWP3A in virus-triggered signaling, which provides insights into preventing excessive immune responses.
VISA/MAVS在抗病毒天然免疫中至关重要。在RNA病毒感染后，VISA通过肿瘤坏死因子受体相关因子（TRAFs）将TBK1募集到线粒体，诱导干扰素调节因子3（IRF3）磷酸化并产生I型干扰素。然而，通过单个TRAFs募集TBK1的机制尚不清楚。在此，我们揭示含PWWP结构域的蛋白3A（PWWP3A）作为RNA病毒触发信号的负调节因子。在病毒感染期间，PWWP3A从细胞核转移到线粒体，与TRAF6竞争结合VISA，从而阻碍TBK1的募集并抑制IRF3激活。然而，PWWP3A介导的抑制程度受E3连接酶PJA2调控，PJA2在感染后诱导PWWP3A降解，突出了抗病毒免疫中复杂的调控网络。一致地，PWWP3A缺陷增强抗病毒反应，Pwwp3a基因敲除小鼠在RNA病毒感染后表现出更高水平的I型干扰素并显示出更强的抵抗力。总之，我们的研究结果揭示了PWWP3A在病毒触发信号中的抑制作用，这为预防过度免疫反应提供了见解。
